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332 Part V: Therapeutic Principles Chapter 22: Pharmacology and Toxicity of Antineoplastic Drugs 333

the E. coli enzyme reduces its immunogenicity and extends its half-life protein C, and protein S, leading to either arterial or venous thrombo-
to 6 days. Pegaspargase is used in patients hypersensitive to the unmod- sis in occasional patients, and a predilection to thrombosis of cortical
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ified enzyme, in doses of 2500 IU/m intramuscularly every 2 weeks. sinus vessels. With more prolonged therapy, bleeding sequelae may
2
Single doses deplete L-asparagine from plasma for 2 to 3 weeks. Some result from inhibition of the synthesis of procoagulant proteins such as
patients develop hypersensitive to both preparations of E. coli enzyme, fibrinogen and factors II, VII, IX, and X. Consequently, monitoring of
particularly if first exposed to the unmodified enzyme; they may be coagulation factors is recommended. High doses of L-asparaginase may
treated with enzyme from Erwinia, which has a low incidence of hyper- cause cerebral dysfunction that manifests as confusion, stupor, seizures,
sensitivity and approximately equal catalytic activity to the E. coli prepa- or coma, and cortical sinus thrombosis has been documented by mag-
154
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ration, but a more rapid clearance. Consequently, the Erwinia enzyme netic resonance imaging scan in such patients. Clinical thromboem-
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must be used in higher doses. bolic episodes may occur in up to 35 percent of children with ALL.
These events are mostly asymptomatic thrombi associated with central
Adverse Effects venous catheters; less frequently, cortical sinus and atrial thrombi may
Reactions to the first dose are uncommon, but after two or more doses of occur. Altered mental status may also result from hyperammonemia
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the unmodified enzyme, hypersensitivity may develop in up to 20 per- and diabetic ketoacidosis. Preexisting clotting abnormalities, such as
cent of patients, varying from urticarial reactions to hypotension, laryn- antiphospholipid antibodies or factor V Leiden deficiency, may predis-
gospasm, and cardiac arrest. Skin testing to predict allergic reactions is pose to thromboembolic complications. 159
helpful in some, but not all, cases, and should be performed to confirm a Acute nonhemorrhagic pancreatitis occurs as a complication of
clinical suspicion of hypersensitivity. Hypersensitive patients may have L-asparaginase treatment, especially in patients who have extreme
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antibodies to L-asparaginase in their plasma. More than half the patients elevations of plasma triglycerides (>2 g/dL). Because L-asparagi-
with such circulating antibodies will not display an overt allergic reac- nase manifests little toxicity in marrow or gastrointestinal mucosa,
tion to the drug, but these patients may have more rapid disappearance it has been used in combination with other drugs that do have such
of drug from plasma and an inadequate clearance of asparagine from toxicities.
plasma and cells, leading to therapeutic failure. Patients who are treated
with L-asparaginase should be observed carefully for several hours IMMUNOMODULATORY DRUGS
after dosing, and epinephrine should be available in case anaphylactic
reactions occur. Anaphylaxis is less likely when E. coli L-asparaginase THALIDOMIDE, LENALIDOMIDE, AND
is given intramuscularly than when it is administered intravenously.
Pegaspargase has much reduced immunogenicity and hypersensitivity POMALIDOMIDE
reactions are uncommon. However, up to 20 percent of patients pre- Thalidomide (α-phthalimidoglutarimide; Fig. 22–5), approved in 1953
viously exposed to unmodified L-asparaginase will develop allergy to as a sedative, was withdrawn shortly thereafter because of its teratogenic-
subsequent pegaspargase, with undetectable enzyme levels in plasma, ity. It causes dysmelia (i.e., stunted limb growth) when used during early
and an additional 8 percent will have silent inactivation of the enzyme. pregnancy. However, it has since reemerged as an important antibacte-
The other major toxic effects of L-asparaginase are a consequence of rial and antitumor agent, with clear effectiveness against leprosy and
the ability of this drug to inhibit protein synthesis in normal tissues. myeloma, especially when combined with other agents. Its analogues,
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Inhibition of protein synthesis in the liver will result in hypoalbumine- lenalidomide and pomalidomide (see Fig. 22–5), have proven to be less
mia, a decrease in clotting factors, a decrease in serum lipoproteins, toxic, and more effective for treating relapsed and refractory patients
and a marked increase in plasma triglycerides. Inhibition of insulin with myeloma. Lenalidomide is highly active in first-line combination
production may lead to hyperglycemia. The clotting abnormalities that therapy with dexamethasone, and also with bortezomib for myeloma,
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are regularly observed as a consequence of L-asparaginase treatment as well as being approved for the treatment of myelodysplasia in patients
include initial decreases in the anticoagulant factors antithrombin III, with the 5q– variant of this syndrome. The newest immunomodulatory

O O O O Figure 22–5. Thalidomide, lenalidomide and pomalido-
H mide. (Reproduced with permission from Brunton L, Chabner
N NH B, and Knollman B: Goodman & Gilman’s The Pharmacologi-
N O N O cal Basis of Therapeutics, 12th ed. New York, NY: McGraw-Hill;
2011.)

O
NH 2
Lenalidomide Thalidomide
A
O O

N O
NH
O O
NH 2
Pomalidomide
B

Kaushansky_chapter 22_p0313-0352.indd 333 9/18/15 10:25 PM